7t84

Publication Abstract from PubMed

Antibodies are essential biological research tools and important therapeutic agents, but some exhibit non-specific binding to off-target proteins and other biomolecules. Such polyreactive antibodies compromise screening pipelines, lead to incorrect and irreproducible experimental results, and are generally intractable for clinical development. Here, we design a set of experiments using a diverse naive synthetic camelid antibody fragment (nanobody) library to enable machine learning models to accurately assess polyreactivity from protein sequence (AUC > 0.8). Moreover, our models provide quantitative scoring metrics that predict the effect of amino acid substitutions on polyreactivity. We experimentally test our models' performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the models allow us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its functional properties. We provide a companion web-server that offers a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.

An in silico method to assess antibody fragment polyreactivity.,Harvey EP, Shin JE, Skiba MA, Nemeth GR, Hurley JD, Wellner A, Shaw AY, Miranda VG, Min JK, Liu CC, Marks DS, Kruse AC Nat Commun. 2022 Dec 7;13(1):7554. doi: 10.1038/s41467-022-35276-4. PMID:36477674^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.